1. Field of the Invention (Technical Field)
The present invention relates to aerosol generation, particularly for generating short bursts of finely divided particles from small portions of cohesive or non-cohesive powders by utilizing rapid decompression of powder particles, including agglomerated particles. Included in the invention are an apparatus and method of producing and using such aerosols.
2. Background Art
Aerosol generation systems are used in several different applications: In industry for injecting powders into tubes for pneumatic transport; in toxicology and industrial hygiene for generating study atmospheres; and in medicine for delivering particulate drugs to patients by the inhalation route. There are more design options available for continually working aerosol generators than for batch-wise devices. Several types of generators originally designed for continuous use include the following: the Venturi tube powder injector, which utilizes pressurized air (Bohnet M., Calculation and design of gas/solid injectors. Powder Technology, 302-313, 1984; Cheng, Y., Barr et al., "A Venturi dispenser as a dry powder generator for inhalation studies," Inhalation Toxicology 1: 365-371, 1989), the Wright dust feeder, which uses a rotating scraper, (Wright, B., "A new dust-feed mechanism", Journal of Scientific Instruments, 27: 12-15, 1950) and various fluidized bed designs, which use blowing air (Drew, R. and Laskin, S., "A new dust-generating system for inhalation studies", American Industrial Hygiene Association Journal, 32: 327-330, 1971; Ebens R. and Vos, M. "A device for the continuous metering of small dust quantities", Staub-Reinhalt der Luft, 28(5): 24-25, 1971).
For dispersion of dry powder medicaments there are three major methods of aerosolization available: Metered dose inhalers (MDI), passive dry powder inhalers (pDPI), and active dry powder inhalers (aDPI). MDIs use a volatile propellant (chlorofluorocarbons) under pressure to aerosolize the medicament. A small volume of the medicament suspended in the liquid propellant is ejected through a nozzle to ambient pressure. The flash boiling resulting from the rapid decompression of the propellant is the main mechanism of aerosolization. pDPIs use the energy of the patient's own breathing to fractionate the medicament into an inhalable aerosol. However, due to the nature of the energy source, it is difficult for some patients, for example with asthma, to achieve a sufficiently high peak respiratory flow rate to overcome agglomeration. This results in an increased deposition of the medicament in the oropharyngeal region. While spacers may alleviate this problem partially, they do not increase the total dose delivered to the lungs. The need for alternative technologies in this field has increased both because the Montreal Protocol will severely restrict the use of ozone-damaging chlorofluorocarbon propellants in MDIs after 1998 (Coyne, T. "Introduction to the CFC problem", Journal of Aerosol Medicine 4: 175-180. 1991), and because a multitude of new drugs, such as peptides, proteins and genes, are currently in development. Many of these potential drugs have been found to be particularly suitable for administration via the inhalation route (Rubsamen, R. "Novel aerosol peptide drug delivery systems", Inhalation Delivery of Therapeutic Peptides and Proteins, NY. 703-731, 1997; Thompson, M. and Weiner-Kronish, J. "General issues in gene delivery via the lung", Inhalation Delivery of Therapeutic Peptides and Proteins, NY., 475-491, 1997). Albeit many of these drugs have their therapeutic action within the airways or the peripheral lung, an increasing number of drugs are intended for distribution in the systemic circulation following absorption in the peripheral lung (alveoli). In the latter case, a high fractional delivery to the peripheral lung is necessary and can be accomplished if the delivery device can deliver the medicament in a particle size range of 1-5 .mu.m at a low inspiratory flow rate (Service, R. "Drug delivery takes a deep breath", Science 277: 1199-1200, 1997). This need created the intense field of innovation in the area of active DPIs (Hickey, A., Concessio, N. et al. "Factors influencing the dispersion of dry powders as aerosols", Pharmaceutical Technology 58-64, 1994).
In active DPIs, the aerosol is either formed directly in a single step from the bulk powder, or in a two-step procedure where larger agglomerates are formed and further fractionated into an inhalable aerosol. Of aDPIs the Venturi tube is a commonly used design. The carrier gas flows through a smooth constriction followed by a gradually widening nozzle. The sonic shock at the constriction and the downstream turbulence are the major aerosolizing forces. The particles can be introduced with the gas stream, or sheared into the airstream at the flow constriction from a smaller particle feed conduit. Due to this design, however, particularly with more adhesive powders, is inevitable plugging of the tube at the flow constriction. Formulation of a less adhesive powder is an important and necessary part of using the Venturi tube design in a DPI. (Service, 1997). Because most other DPIs provide even less energy than Venturi tube designs to de-agglomerate particles, other means of rendering the powder suitable for dispersion and inhalation are used, such as mixing the powder with diluents or excipients. Diluents reduce intra-agglomeration forces, but add to the bulk and cost of the medication (Lucas, P., Clarke, M. et al. "The role of fine particle excipients in pharmaceutical dry powder aerosols", Respiratory Drug Delivery VI, S.C., "Drug deposition of pressurized inhalation aerosols", European Journal of Respiratory Diseases, 63 (Suppl 119): 51-55, 1998).